The central hypothesis of the Program is that the balance between bone resorption and bone formation depends more on the number of bone cells carrying out these processes than on the individual capacities involved. The goal is to further the understanding of osteoporosis by elucidating the molecular, cellular, and genetic mechanisms of bone loss following loss of gonadal function and during aging. In accordance with the central hypothesis, it is proposed that the former is due mainly to excessive osteoclastogenesis and the latter mainly to inadequate osteoblastogenesis. To achieve this goal, three projects, supported by three cores, have been planned. A Project will test the hypothesis that IL/6, and other members of the same cytokine subfamily that share the gp130 signal transducer, are under the inhibitory control of sex steroids, and stimulate osteoblast as well as osteoclast development; a novel mechanism of coupling based on a parallel rather than a serial signal pathway. Another Project will attempt to establish a causal relationship between osteoblastogenesis, bone formation, and bone mass, comparing the SAM P6 and SAM R1 mouse, and determine the relative importance of decreased osteoblast progenitor formation in the bone marrow, and premature osteoblast apoptosis. Another Project will determine the heritability of bone density (measured by DEXA) in the SAM P6 and R1 mouse strains by cross-breeding and comparing the F1 and F2 progeny. Microsatellite repeat markers that distinguish between the P6 and R1 genomes will be used to map and eventually isolate genes associated with osteopenia. One Core will provide scientific, biostatistical, and administrative support to the entire program. One Core will maintain a supply of well-defined animal strains for each investigator. Another Core will provide bone densitometry and bone histomorphometry, both traditional and molecular.